Currently there are many drugs available for the treatment of disorders of the central nervous system. Among these drugs is a category known as antipsychotics which are used for treating serious mental conditions such as schizophrenia and schizophreniform illnesses. Currently available treatments for such conditions are often associated with undesirable adverse events. As such, there remains a need for new compounds that control or eliminate the symptoms of such mental conditions with improved adverse event profiles.
Patients suffering from schizophrenia, a condition of unknown etiology, exhibit a group of both positive and negative symptoms. Positive symptoms include delusions, hallucinations, disordered thoughts, and disorganized speech, while negative symptoms include flat affect, anhedonia, social withdrawal, emotional detachment, cognitive deficits, and poverty of speech. Not only does schizophrenia cause personal suffering by the patient, it also severely affects the patient's occupational and social functions, so that often the patient must be institutionalized, which results in a high cost to society.
A leading hypothesis suggests that the positive symptoms of schizophrenia can be effectively treated by compounds that act as antagonists at certain dopamine receptors. Currently, five principal dopamine receptors (D1-D5) have been identified. Antipsychotic efficacy has been most closely associated with blockade of the D2 class of dopamine receptors. One class of antipsychotic agents known as “typical” antipsychotic agents (eg. haloperidol) are effective in controlling the positive symptoms of schizophrenia. However, they do not adequately treat the negative symptoms and are associated with significant adverse events, principally hyperprolactinemia, tardive dyskinesia, and extrapyramidal side effects (EPS).
One approach to developing better antipsychotic agents, involves the identification of compounds that combine D2 receptor blockade with actions at other receptors. One such agent is clozapine.
Clozapine was the first drug identified as an “atypical” antipsychotic, i.e., a drug effective in treating both the positive and negative symptoms of schizophrenia. Additionally, it has a decreased propensity to induce EPS, hyprolactinemia, and tardive dyskinesia seen with classical, “typical” antipsychotics. Although clozapine is an effective drug, its utility in treating schizophrenia has been limited because of the clinical observation that 1-2% of treated patients developed a potentially fatal blood disorder, agranulocytosis. More recently, olanzapine has been widely accepted as an atypical antipsychotic with relatively few adverse events.
However, weight gain has been observed during treatment with many of the atypical antipsychotic compounds (Wetterling, “Body Weight Gain with Atypical Antipsychotics, A Comparative Review”, Drug Safety 24, 59-73 (2001); Wirshing, et al, “Novel Antipsychotics: Comparison of Weight Gain Liabilities”, J. Clin. Psychiatry 60, 358-363 (1999); Allison, et al, “Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis” Am. J. Psychiatry 156, 1686-1696 (1999); Ganguli, R. Weight gain associated with antipsychotic drugs. J. Clin. Psychiatry 60(suppl. 2), 20-24, (1999). Drugs with the clinical efficacy and safety profile of the atypical antipsychotics but with decreased propensity to induce weight gain would represent improved agents for the treatment of schizophrenia, bipolar disorder, and related disorders.
Atypical antipsychotics like clozapine and olanzapine are D2 receptor antagonists but also interact with other neurotransmitter receptors, including other subtypes for dopamine, and certain receptor subclasses for serotonin, norepinephrine, histamine, and acetylcholine. It is believed that some of these additional receptor activities are responsible for the improved efficacy of the atypical antipsychotics and the adverse events of these agents may be mediated by interactions with others. In particular, it has been suggested that the weight gain effects of the atypical antipsychotics may be due to the blockade of the histamine H1 receptor (Wetterling, “Body Weight Gain with Atypical Antipsychotics, A Comparative Review”, Drug Safety 24, 59-73 (2001); Wirshing, et al, “Novel Antipsychotics: Comparison of Weight Gain Liabilities” J. Clin. Psychiatry 60, 358-363 (1999); Kroeze, et al, “H1 Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs”, Neuropsychopharmacology 28, 519-526 (2003); Orthen-Gambill, N. Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats. Pharmacol. Biochem. Behav. 31, 81-86, (1988). Hence, the development of atypical antipsychotics with decreased affinity for the histamine H1 receptor represents one mechanism for identifying antipsychotics with improved adverse event profiles.
The present invention provides antipsychotic compounds and methods of using those compounds to treat psychotic disorders, in particular, schizophrenia and mood disorders, such as bipolar disorders. These compounds offer certain improvements and advantages over the currently available antipsychotic agents, as for example, but not limited to, improved adverse event profiles. In particular, many of the compounds of this invention have reduced propentsity to cause weight gain because of their decreased affinity for the H1 receptor.